Hearing impairment in TRPV4 knockout mice

doi:10.1016/j.neulet.2005.03.035

Neuroscience Letters

Volume 382, Issue 3, 15 July 2005, Pages 304-308

https://doi.org/10.1016/j.neulet.2005.03.035 Get rights and content

Abstract

Transient receptor potential channel vanilloid subfamily 4 (TRPV4), a member of TRP family, is a mechanosensitive non-selective cation channel. To investigate the role of TRPV4 in the cochlea, the hearing thresholds and effects of acoustic overexposure on the cochlea were examined in TRPV4 knockout mice. TRPV4 knockout mice at age 8 weeks exhibited normal, but those at 24 weeks revealed significantly higher thresholds by auditory brainstem response. The auditory threshold shift was significantly larger in the TRPV4 knockout than in the TRPV4+/+ mice 1 week after the acoustic overexposure of 128 dB SPL. The present findings suggest that disruption of TRPV4 causes delayed-onset hearing loss and makes the cochlea vulnerable to acoustic injury.

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Acknowledgement

The authors are grateful to Dr. Masafumi Okada (Department of Epidemiology, University of Tsukuba) for his advise for statistical analysis.

References (17)

C.C. Greene et al.
DFNA25, a novel locus for dominant non-syndromic hereditary hearing impairment, maps to 12q21-24
Am. J. Hum. Genet.
(2001)
A.M. Jimenez et al.
Age-related loss of distortion product otoacoustic emissions in four mouse strains
Hear. Res.
(1999)
W. Liedtke et al.
Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor
Cell
(2000)
H. Mutai et al.
Vertebrate and invertebrate TRPV-like mechanoreceptors
Cell Calcium
(2003)
M. Suzuki et al.
Impaired pressure sensation in mice lacking TRPV4
J. Biol. Chem.
(2003)
D.P. Corey et al.
TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells
Nature
(2004)
A.D. Güler et al.
Heat-evoked activation of the ion channel, TRPV4
J. Neurosci.
(2002)
R.H. Holme et al.
Progressive hearing loss and increased susceptibility to noise-induced hearing loss in mice carrying a Cdh23 but not a Myo7a mutation
J. Assoc. Res. Otolaryngol.
(2004)

There are more references available in the full text version of this article.

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Genetics of noise-induced hearing loss in the mouse model
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In this vein of investigation, the cytoskeletal protein dystrophin has been shown to be a significant player in X-linked muscular dystrophy (mdx) mice, consistent with previous mapping of the Xp21.2 gene to the same locus, and confirmed by increased NIHL sensitivity in mice with the mutation (Chen et al., 2002). As many other candidate genes regulating development of the stereocilia bundle, however, have conversely failed to demonstrate any phenotype correlation (Tabuchi et al., 2005; Schick et al., 2004). These results stand in stark contrast to key early findings relating to the role of Cdh23 and Xp21.2 in NIHL, and reinforce the complexity and often redundancy of candidate NIHL pathways.
Hearing loss is the most common sensory deficit worldwide, with the majority of preventable injury attributed to noise-induced hearing loss (NIHL). Highly conserved cochlear genetics between humans and mice have made this animal model a high-yield candidate for better characterizing the biologic and genetic underpinnings of human NIHL. This review aims to summarize advances in understanding the genetics of noise-induced hearing loss in mouse models dating from the early 1990s. We review the genetic mechanisms underpinning NIHL as understood in the mouse model, including histopathological and phenotypic associations, molecular and cellular mechanisms of changes in cochlear structures, synaptopathy and neuropathy, and transcriptomics. We describe variations in pathophysiology of hearing loss between mouse strains, with particular emphasis on susceptibility of different strains to different mechanisms of damage after acoustic trauma, and the potential of novel targeted therapeutic approaches for NIHL based on understanding of genetic mechanisms. Finally, we review the current state of research on the cochlear transcriptome after noise exposure in the mouse and implications for translation of these findings to humans.
Role of TRPV4 in skeletal function and its mutant-mediated skeletal disorders
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TRPV4 is a non-selective cation channel that belongs to the TRP super family. This channel can be activated by physiological temperatures and mechanical stimuli. In addition, TRPV4 is modulated by several endogenous mediators including specific lipids, cholesterol and their metabolic products. TRPV4 gene is present in all vertebrates and is widely expressed in tissues originating from ectoderm, endoderm and mesoderm. Although TRPV4 knockout is not lethal, point mutations in TRPV4 cause severe clinical phenotypes with variable penetration in human population. These mutations are mostly “gain-of-function” in nature and primarily affect muscles, bones and peripheral neurons, endorsing TRPV4 as critical regulator of musculoskeletal systems. Here we critically analyze the involvement of TRPV4 in musculoskeletal system. Studies of TRPV4 mutations provide detailed information on musculoskeletal disorders at molecular, cellular and metabolic levels.
TRP channels in COVID-19 disease: Potential targets for prevention and treatment
2021, Chemico-Biological Interactions
Coronavirus disease 2019 [COVID-19] is a global health threat caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV2] that requires two proteins for entry: angiotensin-converting enzyme 2 [ACE2] and -membrane protease serine 2 [TMPRSS2]. Many patients complain from pneumonia, cough, fever, and gastrointestinal (GI) problems. Notably, different TRP channels are expressed in various tissues infected by SARS-CoV-2. TRP channels are cation channels that show a common architecture with high permeability to calcium [Ca²⁺] in most sub-families. Literature review shed light on the possible role of TRP channels in COVID-19 disease. TRP channels may take part in inflammation, pain, fever, anosmia, ageusia, respiratory, cardiovascular, GI and neurological complications related to COVID-19. Also, TRP channels could be the targets for many active compounds that showed effectiveness against SARS-CoV-2. Desensitization or blocking TRP channels by antibodies, aptamers, small molecules or venoms can be an option for COVID-19 prevention and future treatment. This review provides insights into the involvement of TRP channels in different symptoms and mechanisms of SARS-CoV-2 , potential treatments targeting these channels and highlights missing gaps in literature.
Volume sensing in the transient receptor potential vanilloid 4 ion channel is cell type-specific and mediated by an N-terminal volume-sensing domain
2019, Journal of Biological Chemistry
Many retinal diseases are associated with pathological cell swelling, but the underlying etiology remains to be established. A key component of the volume-sensitive machinery, the transient receptor potential vanilloid 4 (TRPV4) ion channel, may represent a sensor and transducer of cell swelling, but the molecular link between the swelling and TRPV4 activation is unresolved. Here, our results from experiments using electrophysiology, cell volumetric measurements, and fluorescence imaging conducted in murine retinal cells and Xenopus oocytes indicated that cell swelling in the physiological range activated TRPV4 in Müller glia and Xenopus oocytes, but required phospholipase A₂ (PLA₂) activity exclusively in Müller cells. Volume-dependent TRPV4 gating was independent of cytoskeletal rearrangements and phosphorylation. Our findings also revealed that TRPV4-mediated transduction of volume changes is dependent by its N terminus, more specifically by its distal-most part. We conclude that the volume sensitivity and function of TRPV4 in situ depend critically on its functional and cell type–specific interactions.
Modulation of the TRPV4 ion channel as a therapeutic target for disease
2017, Pharmacology and Therapeutics
Citation Excerpt :
Despite this, TRPV4−/− mice are viable and fertile, and display only minor phenotypes. These include altered osmosensation; compromised vascular endothelial function; impaired osteoclast differentiation leading to thicker bones; defective stretch sensation in the bladder wall; and mild hearing, pressure and pain sensory impairments (Cortright & Szallasi, 2009; Earley, Heppner, Nelson, & Brayden, 2005; Everaerts et al., 2010; Gevaert et al., 2007; Lechner et al., 2011; Loot et al., 2008; Marrelli, O'Neil, Brown, & Bryan, 2007; Masuyama et al., 2008; Saliez et al., 2008; Sonkusare et al., 2012; Suzuki, Mizuno, Kodaira, & Imai, 2003a; Tabuchi, Suzuki, Mizuno, & Hara, 2005; Vriens et al., 2005). In light of the mild phenotypes observed in TRPV4−/− mice, which would suggest only a minor role of TRPV4 in normal development, it is therefore surprising that mutation of the TRPV4 gene is the direct cause of several disabling and lethal human pathologies, including skeletal dysplasia's and neuropathies (Lamandé et al., 2011; Loukin, Zhou, Su, Saimi, & Kung, 2010; McNulty, Leddy, Liedtke, & Guilak, 2015; Nilius & Voets, 2013).
Transient Receptor Potential Vanilloid 4 (TRPV4) is a broadly expressed, polymodally gated ion channel that plays an important role in many physiological and pathophysiological processes. TRPV4 knockout mice and several synthetic pharmacological compounds that selectively target TRPV4 are now available, which has allowed detailed investigation in to the therapeutic potential of this ion channel. Results from animal studies suggest that TRPV4 antagonism has therapeutic potential in oedema, pain, gastrointestinal disorders, and lung diseases such as cough, bronchoconstriction, pulmonary hypertension, and acute lung injury. A lack of observed side-effects in vivo has prompted a first-in-human trial for a TRPV4 antagonist in healthy participants and stable heart failure patients. If successful, this would open up an exciting new area of research for a multitude of TRPV4-related pathologies. This review will discuss the known roles of TRPV4 in disease, and highlight the possible implications of targeting this important cation channel for therapy.
Modulation of TRPV4 by diverse mechanisms
2016, International Journal of Biochemistry and Cell Biology
Citation Excerpt :
However, TRPV4−/− mice and wild type littermates respond similarly to an acoustic startle, and do not reveal gross abnormalities indicative of vestibular dysfunction (Liedtke and Friedman, 2003). Moreover, 3 month-old homozygous TRPV4−/− mice do not show deficits in auditory brain stem responses or distortion product otoacoustic emissions compared to wild type controls (Cuajungco et al., 2007; Tabuchi et al., 2005). On the other hand, 6 month-old TRPV4−/− mice do show increased auditory brain stem response thresholds and increased vulnerability to acoustic injury compared wild type littermates.
Transient receptor potential ion channels (TRP) are a superfamily of non-selective ion channels which are opened in response to a diverse range of stimuli. The TRP vanilloid 4 (TRPV4) ion channel is opened in response to heat, mechanical stimuli, hypo-osmolarity and arachidonic acid metabolites. However, recently TRPV4 has been identified as an ion channel that is modulated by, and opened by intracellular signalling cascades from other receptors and signalling pathways. Although TRPV4 knockout mice show relatively mild phenotypes, some mutations in TRPV4 cause severe developmental abnormalities, such as the skeletal dyplasia and arthropathy. Regulated TRPV4 function is also essential for healthy cardiovascular system function as a potent agonist compromises endothelial cell function, leading to vascular collapse. A better understanding of the signalling mechanisms that modulate TRPV4 function is necessary to understand its physiological roles. Post translational modification of TRPV4 by kinases and other signalling molecules can modulate TRPV4 opening in response to stimuli such as mechanical and hyposmolarity and there is an emerging area of research implicating TRPV4 as a transducer of these signals as opposed to a direct sensor of the stimuli. Due to its wide expression profile, TRPV4 is implicated in multiple pathophysiological states. TRPV4 contributes to the sensation of pain due to hypo-osmotic stimuli and inflammatory mechanical hyperalsgesia, where TRPV4 sensitizaton by intracellular signalling leads to pain behaviors in mice. In the vasculature, TRPV4 is a regulator of vessel tone and is implicated in hypertension and diabetes due to endothelial dysfunction. TRPV4 is a key regulator of epithelial and endothelial barrier function and signalling to and opening of TRPV4 can disrupt these critical protective barriers. In respiratory function, TRPV4 is involved in cystic fibrosis, cilary beat frequency, bronchoconstriction, chronic obstructive pulmonary disease, pulmonary hypertension, acute lung injury, acute respiratory distress syndrome and cough.In this review we highlight how modulation of TRPV4 opening is a vital signalling component in a range of tissues and why understanding of TRPV4 regulation in the body may lead to novel therapeutic approaches to treating a range of disease states.

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Hearing impairment in TRPV4 knockout mice

Abstract

Section snippets

Acknowledgement

Am. J. Hum. Genet.

Hear. Res.

Cell

Cell Calcium

J. Biol. Chem.

TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells

Nature

Heat-evoked activation of the ion channel, TRPV4

J. Neurosci.

Progressive hearing loss and increased susceptibility to noise-induced hearing loss in mice carrying a Cdh23 but not a Myo7a mutation

J. Assoc. Res. Otolaryngol.